Due to sustained military conflicts in Afghanistan and Iraq over the past decade, there are an increasing number of U.S. military personnel and Veterans returning home with posttraumatic stress disorder (PTSD) and comorbid alcohol use disorders (AUD). If left untreated, Veterans with co-occurring PTSD and substance use disorders are at increased risk for developing other mental health problems (e.g., depression, anxiety), suicidal ideation and attempts, physical health problems, reduced resiliency and military readiness, employment problems, violence, and family/relationship impairment. While mental health services are in place for U.S. service members, substantial gaps in the treatment of co-occurring PTSD and AUD exist and there is little scientific evidence available to guide the provision of care. The proposed study directly addresses this critical knowledge gap by testing the efficacy of doxazosin, a long-acting and selective alpha-1 adrenergic antagonist, as compared to placebo in reducing PTSD and AUD severity among U.S. military personnel who have served in Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn (OEF/OIF/OND). The most common substance use disorder among Veterans is alcohol use disorder (AUD); thus the proposed study targets Veterans with co-occurring PTSD and AUD. The medication to be investigated (doxazosin) represents a novel treatment approach for PTSD/AUD. While prazosin, also an alpha-1 adrenergic antagonist, has been shown to improve sleep and nightmares in military personnel with PTSD and may help reduce substance use severity, it has a short half-life of 2-3 hours and requires multiple doses each day, which is a significant limitation. In several pilot studies, doxazosin has shown promise in significantly reducing symptoms of PTSD and AUD and, in contrast to prazosin, it requires once per day dosing which confers a significant advantage in terms of translating positive findings into routine clinical practice. In this Stage I study, we will (1) employ a two-arm randomized, double-blind, between-groups experimental design that will consist of 12 weeks of treatment with doxazosin or placebo medication; (2) use standardized, repeated dependent measures to rigorously assess PTSD symptomatology and AUD severity at 5 time points (baseline, week 4, week 8, week 12 and 1-month follow-up); (3) measure impairment in associated mental and behavioral health problems (e.g., depression, anxiety, sleep, risky behaviors, family/social functioning); and (4) use functional magnetic resonance imaging (fMRI) to investigate the underlying pathophysiology of comorbid PTSD/AUD and identify prognostic indicators of treatment outcome. To achieve these aims, we have assembled a multidisciplinary team of investigators with nationally-recognized expertise in combat-related PTSD, substance use disorders and neuroimaging who have successfully collaborated in the past and are uniquely qualified to implement this type of investigation. The investigators represent a collaboration of faculty at the Ralph H. Johnson Veterans Affairs (VA) Medical Center and the Medical University of South Carolina (MUSC) in Charleston, SC. The proposed project is directly responsive to the mission of the Consortium to Alleviate PTSD (CAP) in that it seeks to enhance and accelerate research on the treatment of early, chronic and latent onset PTSD and common comorbidities such as AUD. The findings of this study will provide critically needed empirical evidence to help inform clinical practice guidelines and better serve the needs of U.S. service members, Veterans and their families.